Genetic stature puzzle leads to interwoven complex traits

Understanding why African Pygmies are so short — the average adult male height is 4 feet 11 inches — is a longstanding biological mystery. After investigating this genetic puzzle, Sarah Tishkoff, Ph.D., a professor of genetics and biology at the University of Pennsylvania (UP), suggests that variants leading to short stature could be attached to a genetic code beneficial for adapting to life in a tropical environment.

While no single gene tied to short stature was found in her new
study, several genomic regions associated with local adaptation were discovered.

“The adaptive process that produced small body size in Pygmies may be the result of selection for traits other than stature, including early reproduction, metabolism, and immunity,” posits Tishkoff, recipient of an NIH Pioneer Award funded by an NIEHS
grant.

Mining population genomics data

The
Tishkoff Lab specializes in studying genetic variation at the genome level in global populations, but only recently have the tools to uncover complex DNA processes become available. To provide a genome-wide look at the adaptive and genetic basis of short stature in Pygmies, Tishkoff took a multifaceted approach. Her quest was to identify genes responsible for stature determination.

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To start the research, Tishkoff and colleagues compared DNA from a group of Pygmies with that of their Bantu neighbors in Cameroon. The Bantu were chosen as the comparison group, because of their geographic proximity, striking height difference, and history of mixed reproduction with the Pygmies. Genomic regions reflecting Pygmy or Bantu ancestry were differentiated. The researchers found that Pygmies with more Bantu lineage tended to be taller, suggesting a genetic root for height.

Next, the genetic variations unique to Pygmies were explored. The detailed analysis found multiple Pygmy-specific signals of selection in genomic regions, likely tied to local adaptation. On chromosome 3, several genes stood apart from others.

Linking height and disease susceptibility

One gene in particular, the CISH gene, is known to play a role in both growth hormone response and susceptibility to infectious diseases, such as malaria and tuberculosis. Within the intricate links of genetic code, stature could be tied to immunity and ability to reproduce at a young age among the Pygmy population in Cameroon.

Given that Pygmies have an expected lifespan of only 18 years and typically live in microbe-dense tropical forests, their abilities to reproduce early and fight infection faced strong adaptive selection pressure. If the genetic expressions leading to these beneficial responses are also tied to height, short stature could simply be a byproduct of other adaptive traits.

Everything is interconnected, according to Tishkoff. “One of the major challenges in the post-genomic era is understanding the complex web of genetic, developmental, physiological, and environmental interactions underlying continuous trait variation, including susceptibility to disease,” she was quoted as saying in the UP
announcement of her Pioneer Award.

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